Metastasis, the spread and establishment of malignant cells from the primary tumor to distant organs, is the most serious problem in the pathogenesis and clinical management of cancer. Future strategies for the prevention and control of metastasis must confront the now-established fact that cells within the tumor are not identical or static, but are capable of continual change and differ widely in their metastatic potential. The studies outlined in this proposal offer a unique opportunity to monitor, isolate, and characterize directly metastatic variants in their natural setting within the primary tumor and its metastases. Such capabilities are made possible through recently developed monoclonal antibodies (mAbs) which are able to distinguish highly metastatic tumor variants from their nonmetastasizing counterparts. Preliminary biochemical studies of the structure recognized by these antibodies and expressed at high levels on metastatic variants have shown it to be a 72,000-dalton glycoprotein, now designated as Met-72. The sophisticated capabilities of the fluorescent-activated cell sorter (FACS) will be used with these mAbs to determine: (1) how Met-72 expression correlates with the acquisition and efficiency of metastatic activity; (2) when and where metastatic variants arise within the primary tumor; and (3) the role of metastatic variants in the development and maintenance of population equilibrium during tumor growth. Further biochemical characterizations will be performed using two-dimensional isoelectric focusing-SDS gels to determine whether polymorphic forms of Met-72 exist and how they relate to the overall metastatic phenotype. In vivo blocking studies will be performed to determine whether Met-72 antigens represent functional membrane determinants performing necessary interactions during the metastatic process. Other long-term objectives of these studies are the use of these mAbs to rapidly screen environmental and therapeutic conditions which prevent, initiate, or accelerate metastatic variant formation. (O)